Design characteristics, risk of bias, and reporting of randomised controlled trials supporting approvals of cancer drugs by European Medicines Agency, 2014-16: cross sectional analysis
Design characteristics, risk of bias, and reporting of randomised controlled trials supporting approvals of cancer drugs by European Medicines Agency, 2014-16: cross sectional analysis
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DOI：
10.1136/bmj.l5221
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发表时间：
2019-09-18
影响因子：
105.7
通讯作者：
Booth, Christopher M.
中科院分区：
文献类型：
--
作者：
Naci, Huseyin;Davis, Courtney;Booth, Christopher M.
目的检查欧洲药品管理局 (EMA) 批准的抗癌药物关键随机对照试验的设计特征、偏倚风险和报告充分性。设计横断面分析。设置欧洲监管文件、临床试验注册记录、方案、期刊出版物和补充附录。资格标准AP 2014 年至 2016 年间 EMA 批准的新抗癌药物的关键随机对照试验。主要结果测量研究设计特征（随机化、比较器和终点）；使用修订后的 Cochrane 工具的偏倚风险（随机化过程产生的偏倚、偏离预期干预措施、缺失结果数据、结果测量以及报告结果的选择）；报告的充分性（试验方案、出版物、补充附录、临床试验注册记录和监管文件中信息的完整性和一致性）。 结果 2014 年至 2016 年间，EMA 在 54 项关键研究的基础上批准了 32 种新的抗癌药物。其中，41 项 (76%) 是随机对照试验，13 项 (24%) 是非随机研究或单臂研究。 39/41 随机对照试验已发表并纳入我们的研究中。只有 10 项随机对照试验 (26%) 将总体生存率作为主要或共同主要终点进行测量，其余试验则评估替代指标，例如无进展生存期和缓解率。总体而言，19 项随机对照试验 (49%) 被判断其主要结局存在高偏倚风险。对缺失结果数据 (n= 10) 和结果测量 (n= 7) 的担忧是导致偏倚判断高风险的最常见领域。与评估替代疗效终点的随机对照试验相比，评估总生存率作为主要终点的随机对照试验较少（分别为 2/10 (20%) vs 16/29 (55%)）。当分别考虑监管文件和科学文献中的可用信息时，八项随机对照试验的总体偏倚判断风险有所不同（21%），这反映了两种信息来源的报告不足。监管机构发现 10 种药物 (31%) 的偏倚风险评估范围之外还存在其他缺陷。这些缺陷包括临床获益的大小、不适当的比较和非首选研究终点，这些都没有在科学出版物中作为限制披露。 结论 2014 年至 2016 年间构成 EMA 批准新抗癌药物基础的大多数关键研究都是随机对照试验。然而，其中近一半的研究根据其设计、行为或分析被认为存在较高的偏倚风险，其中一些可能是不可避免的，因为癌症试验的复杂性。监管文件和科学文献的报告存在差距。期刊出版物没有承认监管文件中确定的现有证据的主要局限性。
OBJECTIVETo examine the design characteristics, risk of bias, and reporting adequacy of pivotal randomised controlled trials of cancer drugs approved by the European Medicines Agency (EMA).DESIGNCross sectional analysis.SETTINGEuropean regulatory documents, clinical trial registry records, protocols, journal publications, and supplementary appendices.ELIGIBILITY CRITERIAPivotal randomised controlled trials of new cancer drugs approved by the EMA between 2014 and 2016.MAIN OUTCOME MEASURESStudy design characteristics (randomisation, comparators, and endpoints); risk of bias using the revised Cochrane tool (bias arising from the randomisation process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result); and reporting adequacy (completeness and consistency of information in trial protocols, publications, supplementary appendices, clinical trial registry records, and regulatory documents).RESULTSBetween 2014 and 2016, the EMA approved 32 new cancer drugs on the basis of 54 pivotal studies. Of these, 41 (76%) were randomised controlled trials and 13 (24%) were either non-randomised studies or single arm studies. 39/41 randomised controlled trials had available publications and were included in our study. Only 10 randomised controlled trials (26%) measured overall survival as either a primary or coprimary endpoint, with the remaining trials evaluating surrogate measures such as progression free survival and response rates. Overall, 19 randomised controlled trials (49%) were judged to be at high risk of bias for their primary outcome. Concerns about missing outcome data (n= 10) and measurement of the outcome (n= 7) were the most common domains leading to high risk of bias judgments. Fewer randomised controlled trials that evaluated overall survival as the primary endpoint were at high risk of bias than those that evaluated surrogate efficacy endpoints (2/10 (20%) v 16/29 (55%), respectively). When information available in regulatory documents and the scientific literature was considered separately, overall risk of bias judgments differed for eight randomised controlled trials (21%), which reflects reporting inadequacies in both sources of information. Regulators identified additional deficits beyond the domains captured in risk of bias assessments for 10 drugs (31%). These deficits included magnitude of clinical benefit, inappropriate comparators, and nonpreferred study endpoints, which were not disclosed as limitations in scientific publications.CONCLUSIONSMost pivotal studies forming the basis of EMA approval of new cancer drugs between 2014 and 2016 were randomised controlled trials. However, almost half of these were judged to be at high risk of bias based on their design, conduct, or analysis, some of which might be unavoidable because of the complexity of cancer trials. Regulatory documents and the scientific literature had gaps in their reporting. Journal publications did not acknowledge the key limitations of the available evidence identified in regulatory documents.